Tampa, FL (July 25, 2013) -- Many experts believe that chronic fatigue syndrome (CFS) has several root causes including some viruses. Now, lead scientists Shara Pantry, Maria Medveczky and Peter Medveczky of the University of South Florida's Morsani College of Medicine, along with the help of several collaborating scientists and clinicians, have published an article in the Journal of Medical Virology suggesting that a common virus, Human Herpesvirus 6 (HHV-6), is the possible cause of some CFS cases.

Over 95 percent of the population is infected with HHV-6 by age 3, but in those with normal immune systems the virus remains inactive. HHV-6 causes fever and rash (or roseola) in infants during early childhood, and is spread by saliva. In immunocompromised patients, it can reactivate to cause neurological dysfunction, encephalitis, pneumonia and organ failure.

"The good news reported in our study is that antiviral drugs improve the severe neurological symptoms, including chronic pain and long-term fatigue, suffered by a certain group of patients with CFS," said Dr. Medveczky, who is a professor of molecular medicine at USF Health and the study's principal investigator. "An estimated 15,000 to 20,000 patients with this CFS-like disease in the United States alone may ultimately benefit from the application of this research including antiviral drug therapy."

The link between HHV-6 infection and CFS is quite complex. After the first encounter, or "primary infection," all nine known human herpesviruses become silent, or "latent," but may reactivate and cause diseases upon immunosuppression or during aging. A previous study from the Medveczky laboratory showed that HHV-6 is unique among human herpesviruses; during latency, its DNA integrates into the structures at the end of chromosomes known as telomeres.

Furthermore, this integrated HHV-6 genome can be inherited from parent to child, a condition commonly referred to as "chromosomally integrated HHV-6," or CIHHV-6. By contrast, the "latent" genome of all other human herpesviruses converts to a circular form in the nucleus of the cell, not integrated into the chromosomes, and not inheritable by future generations.

Most studies suggest that around 0.8 percent of the U.S. and U.K. population is CIHHV-6 positive, thus carrying a copy of HHV-6 in each cell. While most CIHHV-6 individuals appear healthy, they may be less able to defend themselves against other strains of HHV-6 that they might encounter. Medveczky reports that some of these individuals suffer from a CFS-like illness. In a cohort of CFS patients with serious neurological symptoms, the researchers found that the prevalence of CIHHV-6 was over 2 percent, or more than twice the level found in the general public. In light of this finding, the authors of the study suggest naming this sub-category of CFS "Inherited Human Herpesvirus 6 Syndrome," or IHS.

Medveczky's team discovered that untreated CIHHV-6 patients with CFS showed signs that the HHV-6 virus was actively replicating: determined by the presence of HHV-6 messenger RNA (mRNA), a substance produced only when the virus is active. The team followed these patients during treatment, and discovered that the HHV-6 mRNA disappeared by the sixth week of antiviral therapy with valganciclovir, a drug used to treat closely related cytomegalovirus (HHV-5). Of note, the group also found that short-term treatment regimens, even up to three weeks, had little or no impact on the HHV-6 mRNA level.

The investigators assumed that the integrated virus had become reactivated in these patients; however, to their surprise, they found that these IHS patients were infected by a second unrelated strain of HHV-6.

The USF-led study was supported by the HHV-6 Foundation and the National Institutes of Health.
Further studies are warranted to confirm that immune dysregulation, along with subsequent chronic persistence of the HHV-6 virus, is the root cause of the IHS patients' clinical symptoms, the researchers report.

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I failed to locate the actual study; if someone is able to help me out can they post a link please. Thanks

"An estimated 15,000 to 20,000 patients with this CFS-like disease in the United States alone may ultimately benefit from the application of this research including antiviral drug therapy."

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In a cohort of CFS patients with serious neurological symptoms, the researchers found that the prevalence of CIHHV-6 was over 2 percent, or more than twice the level found in the general public. In light of this finding, the authors of the study suggest naming this sub-category of CFS "Inherited Human Herpesvirus 6 Syndrome," or IHS.

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A very small sub-group then. Presumably the inherent virus had been triggered by something that led to the neurological symptoms and a diagnosis of ME.

Be nice to know if the trigger was thought to have been the same thing for each person: though it might be hard to reach such a conclusion.

I wonder if this is how the wastebasket will be whittled down. Little chips here and little chips there. Nothing dramatic that involves big numbers.

I don't believe they are attributing activation of the inherited virus to aging WillowJ although I don't have the full paper.

Human herpesvirus-6 (HHV-6)A and 6B are ubiquitous betaherpesviruses viruses with lymphotropic and neurotropic potential. As reported earlier, these viruses establish latency by integration into the telomeres of host chromosomes.

Chromosomally integrated HHV-6 (CIHHV-6) can be transmitted vertically from parent to child. Some CIHHV-6 patients are suffering from neurological symptoms, while others remain asymptomatic.

Four patients with CIHHV-6 and CNS dysfunction were treated with valganciclovir or foscarnet. HHV-6 replication was detected by reverse transcriptase polymerase chain reaction amplification of a late envelope glycoprotein.

In this study we also compared the inherited and persistent HHV-6 viruses by DNA sequencing. The prevalence of CIHHV-6 in this cohort of adult patients from the USA suffering from a wide range of neurological symptoms including long-term fatigue were found significantly greater than the reported 0.8% in the general population.

Long-term antiviral therapy inhibited HHV-6 replication as documented by loss of viral mRNA production. Sequence comparison of the mRNA and the inherited viral genome revealed that the transcript is produced by an exogenous virus.

In conclusion, the data presented here document that some individuals with CIHHV-6 are infected persistently with exogenous HHV-6 strains that lead to a wide range of neurological symptoms; the proposed name for this condition is inherited herpesvirus 6 syndrome or IHS.

“Chromosomally integrated HHV-6” (CIHHV-6) is an inherited condition in which the complete HHV-6 genome is integrated into the telomere of every chromosome.

The condition affects around 0.8% of the population in the US and UK, but appears to affect a greater percentage of patients and may be overly represented in patients with encephalitis and other conditions (Pellett 2011), and some CIHHV-6 individuals may have difficulty defending themselves against community acquired strains of HHV-6, resulting in persistent infection, cognitive dysfunction and fatigue (Pantry 2013, Montoya 2012).

Integrated HHV-6 can be inherited from either parent, so families with one carrier (father or mother) have a 50% chance of passing the condition on to each child.

CIHHV-6 individuals will always have a very high viral load—generally over 1 million copies per ml on whole blood samples, and over 3,000 copies/ml in serum.

This high viral load can sometimes be mistaken for an active HHV-6 infection, and therefore can result in the unnecessary administration of potentially toxic antivirals to patients not actually suffering from a viral infection.

Also (from the article on the same site I linked to in my post above to Willow):

HHV-6 DNA levels are generally quite low in the blood, so it is easy to differentiate a CIHHV-6 patient from one who has an active infection through the use of a whole blood PCR DNA test. Only transplant patients with encephalitis or graft vs host disease (GVHD) or patients with drug-induced hypersensitivity syndrome (DIHS) have been reported to have DNA loads comparable to those found in patients with CIHHV-6, or over 1 million copies per ml in whole blood. CIHHV-6 individuals will always test positive in a PCR DNA test of the serum and whole blood, but can test negative for HHV-6 DNA in plasma or spinal fluid (which is generally cell free) depending on the level of sensitivity of the assay. An asymptomatic or mildly ill CIHHV-6 patient might have a viral load of 200 to 3000 copies/ml in plasma, depending on the amount of time that passes between the blood draw and processing.If your physician suspects that you have CIHHV-6, and you have had the following laboratory results on more than one occasion:

A whole blood quantitative PCR test > 500,000 copies per mL

A serum blood test of over 3,000 copies per mL

A plasma blood test of over 1000 copies per mL

Click HERE to learn more about joining the CIHHV-6 patient registry. If you are a patient with CIHHV-6, or a physician interested in participating in research studies pertaining to CIHHV-6, please contact us.

Over 95 percent of the population is infected with HHV-6 by age 3, but in those with normal immune systems the virus remains inactive.

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I wonder, if you're one of the 5% who don't have HHV-6 by age 3, if there is any unique consequence to initialy acquiring this virus much later in life, perhaps at a time when one’s immune system has been weakened by some other factor.

I wonder, if you're one of the 5% who don't have HHV-6 by age 3, if there is any unique consequence to initialy acquiring this virus much later in life, perhaps at a time when one’s immune system has been weakened by some other factor.

Quite a few viruses cause a mono like illness, not just EBV (HHV4). If inherited HHV-6 is causal (and the evidence is only suggestive) then what about other herpes viruses, and indeed other viruses that have a latent mode like enteroviruses?

In EBV (I think) and mumps adult infections are much more serious. Children have different immune responses to adults. Its not so much the virus, its our immune systems.

I came across an article recently which pointed out that during certain phases of the immune response (e.g. during the beginning stages of an infection) it seems to be beneficial to have less active natural killer cells.

This reminded me that CFS patients have lower natural killer cell activity. Perhaps it is an adaptation to the presence of a virus which never fully takes hold and/or the immune system is stuck in the beginning stages of the response?

Presumably the inherent virus had been triggered by something that led to the neurological symptoms and a diagnosis of ME.

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Hi Firestormm,You've probably worked it out now, from the second paper that you posted, but I think you may have missed this from the first paper:

"The investigators assumed that the integrated virus had become reactivated in these patients; however, to their surprise, they found that these IHS patients were infected by a second unrelated strain of HHV-6."

So it seems that they are saying that infection with a second exogenous HHV-6 virus leads to, or triggers, the CFS symptoms in the patients with the inherited virus.

Here's what I don't get. I looked around for this HHV-6 and it seems there were a lot of things that it could be responsible for including, now, within this small subset of IHS patients: the symptoms previously attributed to ME.

How would someone know if a subsequent HHV-6 infection had occurred in the first place? As a patient I mean what would possibly be an recognisable HHV-6-style infection? I mean these aren't invisible are they - or are they?

Only I found this which talks about HHV-6 A and HHV-6 B. And am now kerfuddled. HHV-6A is the one responsible for the childhood roseola and HHV-6B is symptom-free but could be the one that triggers the ME-like-severe neurological symtpoms in IHS patients.

Unless the article is wrong of course or the initial post above simply doesn't equate A and B or something.

This HHV6 problem from chromosome is not the only problem. Remember all other infections and reactivations found in CFS patients. Think about this study: February 19, 2013: De Meirleir, et al., Plasmacytoid Dendritic Cells in the Duodenum of Individuals Diagnosed with Myalgic Encephalomyelitis Are Uniquely Immunoreactive to Antibodies to Human Endogenous Retroviral Proteins It all points out to immune dysfunction. That is the key player. It is a litle scary. It looks like HIV problems.

From reading this it seems that this inherited viral DNA could be a strong precipitating factor in contracting ME/CFS but i find it questionable as to it being a universal cause of all the symptoms. It seems more likely to me that the cause for many people lies in a dysregulated immune response after a viral infection - possibly autoimmunity - which in turn could lead to viral reactivation compounding the illness.
However in those where the onset was slow and things such as stress acted as a lone trigger this could be a clue as to the development of the illness and could also represent a sub-group who may respond well to anti-viral therapy but not B-cell depletion.
Food for thought if nothing else.
Andrew (19)

From reading this it seems that this inherited viral DNA could be a strong precipitating factor in contracting ME/CFS...

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They say that only 2 percent of their CFS cohort had the inherited virus (CIHHV-6):

"In a cohort of CFS patients with serious neurological symptoms, the researchers found that the prevalence of CIHHV-6 was over 2 percent, or more than twice the level found in the general public."

As far as I can see, the details in this thread don't indicate how many people with CIHHV-6 experience CFS-like symptoms, except for the following (my emphasis):

"While most CIHHV-6 individuals appear healthy, they may be less able to defend themselves against other strains of HHV-6 that they might encounter. Medveczky reports that some of these individuals suffer from a CFS-like illness."

"The prevalence of CIHHV-6 in this cohort of adult patients from the USA suffering from a wide range of neurological symptoms including long-term fatigue were found significantly greater than the reported 0.8% in the general population."

its great to finally see another study in this area as its HHV-6 was always one I'd been interested in in ME/CFS and thought previously studies showed some hope of bringing some very good info in. Then all had gone quite in this field and this area being unresearched again for so long.

Here's what I don't get. I looked around for this HHV-6 and it seems there were a lot of things that it could be responsible for including, now, within this small subset of IHS patients: the symptoms previously attributed to ME.

How would someone know if a subsequent HHV-6 infection had occurred in the first place? As a patient I mean what would possibly be an recognisable HHV-6-style infection? I mean these aren't invisible are they - or are they?

Only I found this which talks about HHV-6 A and HHV-6 B. And am now kerfuddled. HHV-6A is the one responsible for the childhood roseola and HHV-6B is symptom-free but could be the one that triggers the ME-like-severe neurological symtpoms in IHS patients.

Unless the article is wrong of course or the initial post above simply doesn't equate A and B or something.

Could be me. Long morning

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Firestormm.. It used to be known there was two types of HHV6 .. that being A and B (as there hasnt been any ME/CFS HHV-6 research being done for years, I havent kept up on HHV-6 stuff but I'll say what I used to know from where I was researching into that area in the past).

Everyone gets infected with HHV6 and with one of these varieties (on rare occassions a person could be infected with both but what happens is in getting one of these, usually gives immunity to the person from getting the other kind, so its rare to have both. HHV-6 A wasnt common in the general community at all (it may of been as low as 4%.. I cant remember but the stat was quite low), so most normal people carry HHV-6 B. One CFS study thou found most ME/CFS people were carrying HHV-6A (the number was above 75% so I thought the high number whatever it was and the differences to the normal pop, was quite a startling find.
They also found hat some of us with CFS actually carried both..

I dont know what happened as as far as I know, this field then went cold with no follow up studies being done in this ME/CFS area back when i was interested in HHV6 ... i do know in most research of HHV6 (non ME/CFS research) that they werent even splitting up the two types to look at so research into HHV6A also seemed abandoned. Any info out there seemed to be on HHV6-B

The investigators assumed that the integrated virus had become reactivated in these patients; however, to their surprise, they found that these IHS patients were infected by a second unrelated strain of HHV-6.

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sights.. this study is not really telling us like most HHV-6 studies.. what HHV6 they refering too.. Was the ME/CFS people being looked at nearly all carrying HHV6-A?? instead of HHV6-B which most do? I dont find it surprising at all that it was found that the patients were infected by a second strain of HHV-6 seeing a CFS study in the past, way back, showed that some of us were surprisingly carrying both.

Ive had a couple of different people who had issues with HHV6 reaction over the years tell me due to my symptoms that they think I have this going on too.. unfortunately Ive found no doctor to give me a test for HHV6 at all.